Goodsmith Nichole, Guo Xinzheng V, Vandal Omar H, Vaubourgeix Julien, Wang Ruojun, Botella Hélène, Song Shuang, Bhatt Kamlesh, Liba Amir, Salgame Padmini, Schnappinger Dirk, Ehrt Sabine
Department of Microbiology and Immunology, Weill Cornell Medical College, New York, New York, United States of America.
Department of Medicine, Center for Emerging Pathogens, Rutgers, The State University of New Jersey, New Jersey Medical School, Newark, New Jersey, United States of America.
PLoS Pathog. 2015 Feb 6;11(2):e1004645. doi: 10.1371/journal.ppat.1004645. eCollection 2015 Feb.
The identification of Mycobacterium tuberculosis genes necessary for persistence in vivo provides insight into bacterial biology as well as host defense strategies. We show that disruption of M. tuberculosis membrane protein PerM (Rv0955) resulted in an IFN-γ-dependent persistence defect in chronic mouse infection despite the mutant's near normal growth during acute infection. The perM mutant required increased magnesium for replication and survival; incubation in low magnesium media resulted in cell elongation and lysis. Transcriptome analysis of the perM mutant grown in reduced magnesium revealed upregulation of cell division and cell wall biosynthesis genes, and live cell imaging showed PerM accumulation at the division septa in M. smegmatis. The mutant was acutely sensitive to β-lactam antibiotics, including specific inhibitors of cell division-associated peptidoglycan transpeptidase FtsI. Together, these data implicate PerM as a novel player in mycobacterial cell division and pathogenesis, and are consistent with the hypothesis that immune activation deprives M. tuberculosis of magnesium.
鉴定结核分枝杆菌在体内持续存在所必需的基因，有助于深入了解细菌生物学以及宿主防御策略。我们发现，尽管结核分枝杆菌膜蛋白PerM（Rv0955）突变体在急性感染期间生长近乎正常，但在慢性小鼠感染中，其破坏会导致依赖干扰素-γ的持续存在缺陷。perM突变体在复制和存活时需要增加镁的含量；在低镁培养基中培养会导致细胞伸长和裂解。对在低镁环境中生长的perM突变体进行转录组分析，发现细胞分裂和细胞壁生物合成基因上调，活细胞成像显示PerM在耻垢分枝杆菌的分裂隔膜处积累。该突变体对β-内酰胺类抗生素高度敏感，包括与细胞分裂相关的肽聚糖转肽酶FtsI的特异性抑制剂。这些数据共同表明PerM是分枝杆菌细胞分裂和发病机制中的一个新角色，并且与免疫激活使结核分枝杆菌缺乏镁的假说一致。
